The present invention relates to a pyrrolo[1,2-b]pyridazine derivative effective for inhibiting sPLA2-mediated fatty acid release.
sPLA2 (secretory phospholipase A2) is an enzyme that hydrolyzes membrane phospholipids and has been considered to be a rate-determining enzyme that governs the so-called arachidonate cascade where arachidonic acid, the hydrolysis product, is the starting material. Moreover, lysophospholipids that are produced as by-products in the hydrolysis of phospholipids have been known as important mediators in cardiovascular diseases. Accordingly, in order to normalize excess functions of the arachidonate cascade and the lysophospholipids, it is important to develop compounds which inhibit the liberation of sPLA2-mediated fatty acids (for example, arachidonic acid), namely, compounds which inhibit the activity or production of sPLA2. Such compounds are useful for general treatment of symptoms, which are induced and/or sustained by an excess formation of sPLA2, such as septic shock, adult respiratory distress syndrome, pancreatitis, injury, bronchial asthma, allergic rhinitis, chronic rheumatism, arteriosclerosis, cerebral apoplexy, cerebral infarction, inflammatory colitis, psoriasis, cardiac insufficiency, cardiac infarction, and so on. The participation of sPLA2 is considered to be extremely wide and, besides, its action is potent.
There are known, as examples of sPLA2 inhibitor, indole derivatives in EP-620214 (JP Laid-Open No. 010838/95), EP-620215 (JP Laid-Open No. 025850/95), EP-675110 (JP Laid-Open No. 285933/95), WO 96/03376, and WO 99/00360; indene derivatives in WO 96/03120; indolizine derivatives in WO 96/03383; naphthalene derivatives in WO 97/21664 and WO 97/21716; tricyclic derivatives in WO 98/18464; pyrazole derivatives in WO 98/24437; phenylacetamide derivatives in WO 98/24756; phenyl glyoxamide derivatives in WO 98/24794; pyrrole derivatives in WO 98/25609.
The present invention provides pyrrolo[1,2-b]pyridazine derivatives having sPLA2 inhibiting activity and being useful for treatment of septic shock, adult respiratory distress syndrome, pancreatitis, injury, bronchial asthma, allergic rhinitis, chronic rheumatism, arterial sclerosis, cerebral hemorrhage, cerebral infarction, inflammatory colitis, psoriasis, cardiac failure, and cardiac infarction.
The present invention relates to i) a compound represented by the formula (I): 
wherein R1 is a group selected from (a) C6 to C20 alkyl, C6 to C20 alkenyl, C6 to C20 alkynyl, carbocyclic groups, and heterocyclic groups, (b) the groups represented by (a) each substituted independently with at least one group selected from non-interfering substituents, and (c) xe2x80x94(L1)xe2x80x94R6 wherein L1 is a divalent linking group of 1 to 18 atom(s) selected from hydrogen atom(s), nitrogen atom(s), carbon atom(s), oxygen atom(s), and sulfur atom(s), and R6 is a group selected from the groups (a) and (b);
R2 is hydrogen atom or a group containing 1 to 4 non-hydrogen atoms;
R3 is xe2x80x94(L2)-(acidic group) wherein L2 is an acid linker having an acid linker length of 1 to 5;
R4 and R5 are selected independently from hydrogen atom, non-interfering substituents, carbocyclic groups, carbocyclic groups substituted with a non-interfering substituent(s), heterocyclic groups, and heterocyclic groups substituted by a non-interfering substituent(s); and
RA is a group represented by the formula: 
xe2x80x83wherein L7 is a divalent linker group selected from a bond or a divalent group selected from xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94COxe2x80x94, R27 and R28 are independently hydrogen atom, C1 to C3 alkyl or a halogen; X and Y are independently an oxygen atom or a sulfur atom; and Z is xe2x80x94NH2 or xe2x80x94NHNH2; the prodrugs thereof, or their pharmaceutically acceptable salts; or their solvates.
In more detail, the present invention relates to ii) a compound represented by the formula (II): 
where R7 is xe2x80x94(CH2)mxe2x80x94R2 wherein m is an integer from 1 to 6, and R12 is (d) a group represented by the formula: 
wherein a, c, e, n, q, and t are independently an integer from 0 to 2, R13 and R14 are independently selected from a halogen, C1 to C10 alkyl, C1 to C10 alkyloxy, C1 to C10 alkylthio, aryl, heteroaryl, and C1 to C1 0 haloalkyl, xcex1 is an oxygen atom or a sulfur atom, L5 is xe2x80x94(CH2)vxe2x80x94, xe2x80x94Cxe2x95x90Cxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94Oxe2x80x94, or xe2x80x94Sxe2x80x94, v is an integer from 0 to 2, xcex2 is xe2x80x94CH2xe2x80x94 or xe2x80x94(CH2)2xe2x80x94, xcex3 is an oxygen atom or a sulfur atom, b is an integer from 0 to 3, d is an integer from 0 to 4, f, p, and w are independently an integer from 0 to 5, g is an integer from 0 to 2, r is an integer from 0 to 7, and u is an integer from 0 to 4, or is (e) a member of (d) substituted with at least one substituent selected from the group consisting of C1 to C6 alkyl, C1 to C6 alkyloxy, C1 to C6 haloalkyloxy, C1 to C6 haloalkyl, aryl, and a halogen;
R8 is C1 to C3 alkyl, C2 to C3 alkenyl, C3 to C4 cycloalkyl, C3 to C4 cycloalkenyl, C1 to C2 haloalkyl, C1 to C3 alkyloxy, or C1 to C3 alkylthio;
R9 is xe2x80x94(L3)xe2x80x94R15 wherein L3 is represented by the formula: 
xe2x80x83wherein M is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94N(R24)xe2x80x94, or xe2x80x94Sxe2x80x94, R16 and R17 are independently hydrogen atom, C1 to C10 alkyl, aryl, aralkyl, alkyloxy, haloalkyl, carboxy, or a halogen, and R24 is hydrogen atom or C1 to C6 alkyl, and R15 is represented by the formula: 
xe2x80x83wherein R18 is hydrogen atom, a metal, or C1 to C10 alkyl, R19 is independently hydrogen atom, or C1 to C10 alkyl, and t is an integer from 1 to 8;
R10 and R11 are independently hydrogen atom or a non-interfering substituent selected from C1 to C8 alkyl, C2 to C8 alkenyl, C2 to C8 alkynyl, C7 to C12 aralkyl, C7 to C12 alkaryl, C3 to C8 cycloalkyl, C3 to C8 cycloalkenyl, phenyl, tolyl, xylyl, biphenylyl, C1 to C8 alkyloxy, C2 to C8 alkenyloxy, C2 to C8 alkynyloxy, C2 to C12 alkyloxyalkyl, C2 to C12 alkyloxyalkyloxy, C2 to C12 alkylcarbonyl, C2 to C12 alkylcarbonylamino, C2 to C12 alkyloxyamino, C2 to C12 alkyloxyaminocarbonyl, C1 to C12 alkylamino, C1 to C6 alkylthio, C2 to C12 alkylthiocarbonyl, C1 to C8 alkylsulfinyl, C1 to C8 alkylsulfonyl, C2 to C8 haloalkyloxy, C1 to C8 haloalkylsulfonyl, C2 to C8 haloalkyl, C1 to C8 hydroxyalkyl, xe2x80x94C(O)O(C1 to C8 alkyl), xe2x80x94(CH2)zxe2x80x94Oxe2x80x94(C1 to C8 alkyl), benzyloxy, aryloxy, aryloxy C1 to C8 alkyl, arylthio, arylthio C1 to C8 alkyl, cyano C1 to C8 alkyl, xe2x80x94(CONHSO2R25), xe2x80x94CHO, amino, amidino, halogen, carbamyl, carboxyl, carbalkoxy, xe2x80x94(CH2)zxe2x80x94CO2H, cyano, cyanoguanidinyl, guanidino, hydrazido, hydrazino, hydrazide, hydroxy, hydroxyamino, iodo, nitro, phosphono, xe2x80x94SO3H, thioacetal, thiocarbonyl, or carbonyl, R25 is C1 to C6 alkyl or aryl, z is an integer from 1 to 8; and RB is a group represented by the formula: 
xe2x80x83wherein Z is the same as defined above; the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates.
When the above b, d, f, p, r, u, and/or w are 2 or more, a plural number of R13 or R14 may be different from one another. When R13 is a substituent on the naphthyl group, the substituent may be substituted at any arbitrary position on the naphthyl group.
iii) A compound, the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates as described in above i) or ii), wherein said R1 and R7 are independently represented by the formula: 
wherein R13, R14, b, d, f, g, p, r, u, w, xcex1, xcex2, and xcex3 are the same as defined above, L6 is a bond, xe2x80x94CH2xe2x80x94, xe2x80x94Cxe2x95x90Cxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94Oxe2x80x94, or xe2x80x94Sxe2x80x94.
When the above b, d, f, p, r, u, and/or w are 2 or more, a plural number of R13 or R14 may be different from one another. When R13 is a substituent on the naphthyl group, the substituent may be substituted at any arbitrary position on the naphthyl group.
iv) A compound, the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates as described in any one of i) to iii), wherein R2 and R8 are C1 to C3 alkyl or C3 to C4 cycloalkyl.
v) A compound, the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates as described in any one of i) to iv), wherein the L2 and L3 are xe2x80x94Oxe2x80x94CH2xe2x80x94.
vi) A compound represented by the formula (III): 
wherein R20 is a group represented by the formula: 
wherein L6 is a bond, xe2x80x94CH2xe2x80x94, xe2x80x94Cxe2x95x90Cxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94Oxe2x80x94, or xe2x80x94Sxe2x80x94; R13 and R14 are independently selected from a halogen, C1 to C10 alkyl, C1 to C10 alkyloxy, C1 to C10 alkylthio, aryl, heteroaryl, and C1 to C10 haloalkyl; b is an integer from 0 to 3, d is an integer from 0 to 4, f, p, and w are independently an integer from 0 to 5, g is an integer from 0 to 2, r is an integer from 0 to 7, u is an integer from 0 to 4; xcex1 is an oxygen atom or a sulfur atom; xcex2 is xe2x80x94CH2xe2x80x94 or xe2x80x94(CH2)2xe2x80x94; and xcex3 is an oxygen atom or a sulfur atom;
R21 is C1 to C3 alkyl or C3 to C4 cycloalkyl;
L4 is xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94Sxe2x80x94CH2xe2x80x94, xe2x80x94N(R24)xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94CH(CH3)xe2x80x94, or xe2x80x94Oxe2x80x94CH((CH2)2Ph)xe2x80x94 wherein R24 is hydrogen atom or C1 to C6 alkyl and Ph is phenyl;
R22 is xe2x80x94COOH, xe2x80x94SO3H, or P(O)(OH)2;
R23 is hydrogen atom, C1 to C6 alkyl, C7 to C12 aralkyl, C1 to C6 alkyloxy, C1 to C6 alkylthio, C1 to C6 hydroxyalkyl, C2 to C6 haloalkyloxy, halogen, carboxy, C1 to C6 alkyloxycarbonyl, aryloxy, aryloxy C1 to C8 alkyl, arylthio, arylthio C1 to C8 alkyl, cyano C1 to C8 alkyl, a carbocyclic group, or a heterocyclic group; and
RB is a group represented by the formula: 
xe2x80x83wherein Z is xe2x80x94NH2 or xe2x80x94NHNH2; the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates.
When the above b, d, f, p, r, u, and/or w are 2 or more, a plural number of R13 or R14 may be different from one another. When R13 is a substituent on the naphthyl group, the substituent may be substituted at any arbitrary position on the naphthyl group.
vii) A compound represented by the formula (IV): 
wherein R20 is a group represented by the formula: 
wherein L6 is a bond, xe2x80x94CH2xe2x80x94, xe2x80x94Cxe2x95x90Cxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94Oxe2x80x94, or xe2x80x94Sxe2x80x94; R13 and R14 are independently selected from a halogen, C1 to C10 alkyl, C1 to C10 alkyloxy, C1 to C10 alkylthio, aryl, heteroaryl, and C1 to C10 haloalkyl; b is an integer from 0 to 3, d is an integer from 0 to 4, f, p, and w are independently an integer from 0 to 5, g is an integer from 0 to 2, r is an integer from 0 to 7, u is an integer from 0 to 4; xcex1 is an oxygen atom or a sulfur atom; xcex2 is xe2x80x94CH2xe2x80x94 or xe2x80x94(CH2)2xe2x80x94; and xcex3 is an oxygen atom or a sulfur atom;
R21 is C1 to C3 alkyl or C3 to C4 cycloalkyl;
R23 is hydrogen atom, C1 to C6 alkyl, C7 to C12 aralkyl, C1 to C6 alkyloxy, C1 to C6 alkylthio, C1 to C6 hydroxyalkyl, C2 to C6 haloalkyloxy, halogen, carboxy, C1 to C6 alkyloxycarbonyl, aryloxy, aryloxy C1 to C8 alkyl, arylthio, arylthio C1 to C8 alkyl, cyano C1 to C8 alkyl, a carbocyclic group, or a heterocyclic group;
RB is a group represented by the formula: 
xe2x80x83wherein Z is xe2x80x94NH2 or xe2x80x94NHNH2; and
k is an integer from 1 to 3; the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates.
viii) A compound, the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates as described in vi), wherein L4 is xe2x80x94Oxe2x80x94CH2xe2x80x94.
ix) A compound, the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates as described in any one of i) to viii), wherein RA and RB are xe2x80x94COCONH2xe2x80x94.
x) A compound, the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates as described in any one of i) to viii), wherein RA and RB are xe2x80x94CH2CONH2xe2x80x94.
xi) A compound, the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates as described in any one of i) to viii) wherein RA and RB are xe2x80x94CH2CONHNH2xe2x80x94.
xii) A prodrug as described in any one of i) to viii) which of an is ester type.
xiii) A pyrrolo[1,2-b]pyridazine compound selected from the group consisting of:
Methyl (5-aminooxalyl-7-benzyl-6-ethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
(5-aminooxalyl-7-benzyl-6-ethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetic acid,
Sodium (5-aminooxalyl-7-benzyl-6-ethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
Methyl (5-aminooxalyl-7-benzyl-6-ethyl-2-methylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
(5 -aminooxalyl-7-benzyl-6-ethyl-2-methylpyrrolo[1,2-b]pyridazine-4-yloxy)acetic acid,
Methyl (5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo[1,2-b]pyridazine-4-yloxy) acetate,
Ethyl (5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo[1,2-b]pyridazine-4-yloxy) acetate,
2-(Morpholine4-yl)ethyl (5aminooxalyl-7-benzyl-2,6-dimethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
(5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetic acid,
Sodium (5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
Methyl (5-aminooxalyl-7-benzyl-6-methyl-2-phenylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
(5-aminooxalyl-7-benzyl-6-methyl-2-phenylpyrrolo[1,2-b]pyridazine-4-yloxy)acetic acid,
Methyl (5-aminooxalyl-7-benzyl-6-ethyl-2-phenylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
(5-aminooxalyl-7-benzyl-6-ethyl-2-phenylpyrrolo[1,2-b]pyridazine-4-yloxy)acetic acid,
Methyl [5-aminooxalyl-6-ethyl-7-(2-fluorobenzyl)-2-phenylpyrrolo[1,2-b]pyridazine-4-yloxy]acetate,
[5-aminooxalyl-6-ethyl-7-(2-fluorobenzyl)-2-phenylpyrrolo[1,2-b]pyridazine-4-yloxy]acetic acid,
Methyl [5-aminooxalyl-7-benzyl-6-ethyl-2-(4-fluorophenyl)pyrrolo[1,2-b]pyridazine-4-yloxy]acetate,
[5-aminooxalyl-7-benzyl-6-ethyl-2-(4-fluorophenyl)pyrrolo[1,2-b]pyridazine-4-yloxy]acetic acid,
Methyl (5-aminooxalyl-7-benzyl-6-ethyl-2-phenoxymethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
(5-aminooxalyl-7-benzyl-6-ethyl-2-phenoxymethylpyrrolo[1,2-b]pyridazine4-yloxy)acetic acid,
Methyl [5-aminooxalyl-7-benzyl-6-ethyl-2-(4-methoxyphenyl)pyrrolo[1,2-b]pyridazine-4-yloxy]acetate,
[5-aminooxalyl-7-benzyl-6-ethyl-2-(4-methoxyphenyl)pyrrolo[1,2-b]pyridazine-4-yloxy]acetic acid,
Methyl [5-aminooxalyl-6-ethyl-2-methyl-7-(2-phenylbenzyl)pyrrolo[1,2-b]pyridazine-4-yloxy]acetate,
[5-aminooxalyl-6-ethyl-2-methyl-7-(2-phenylbenzyl)pyrrolo[1,2-b]pyridazine-4-yloxy]acetic acid,
Methyl [5-aminooxalyl-6-ethyl-2-methyl-7-(3-phenoxybenzyl)pyrrolo[1,2-b]pyridazine-4-yloxy]acetate,
[5-aminooxalyl-6-ethyl-2-methyl-7-(3 -phenoxybenzyl)pyrrolo[1,2-b]pyridazine-4-yloxy]acetic acid,
Methyl (5-aminooxalyl-7-benzyl-6-methyl-2-propylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
(5-aminooxalyl-7-benzyl-6-methyl-2-propylpyrrolo[1,2-b]pyridazine-4-yloxy)acetic acid,
Methyl (5-aminooxalyl-2,7-dibenzyl-6-methylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
(5-aminooxalyl-2,7-dibenzyl-6-methylpyrrolo[1,2-b]pyridazine-4-yloxy)acetic acid,
Methyl [5-aminooxalyl-2,6-dimethyl-7-[2-(4-fluorophenyl)benzyl]pyrrolo[1,2-b]pyridazine-4-yloxy]acetate, and
[5-aminooxalyl-2,6-dimethyl-7-[2-(4-fluorophenyl)benzyl]pyrrolo[1,2-b]pyridazine-4-yloxy]acetic acid,
and the prodrugs thereof; or their pharmaceutically acceptable salts; their parent acids; or their solvates.
xiv) A pyrrolo[1,2-b]pyridazine compound selected from the group consisting of:
Methyl(5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
Ethyl (5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo[1,2-b]pyridazine4-yloxy)acetate,
2-(Morpholine-4-yl)ethyl (5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
Sodium (5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
(5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetic acid,
Methyl (5-aminooxalyl-7-benzyl-6-methyl-2-phenylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
Ethyl (5-aminooxalyl-7-benzyl-6-methyl-2-phenylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
2-(Morpholine-4-yl)ethyl (5-aminooxalyl-7-benzyl-6-methyl-2-phenylpyrrolo [1,2-b]pyridazine-4-yloxy)acetate,
Sodium (5-aminooxalyl-7-benzyl-6-methyl-2-phenylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
(5-aminooxalyl-7-benzyl-6-methyl-2-phenylpyrrolo[1,2-b]pyridazine-4-yloxy)acetic acid,
Methyl (5-aminooxalyl-7-benzyl-6-ethyl-2-phenoxymethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
Ethyl (5-aminooxalyl-7-benzyl-6-ethyl-2-phenoxymethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
2-(Morpholine-4-yl)ethyl 5-aminooxalyl-7-benzyl-6-ethyl-2-phenoxymethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
Sodium (5-aminooxalyl-7-benzyl-6-ethyl-2-phenoxymethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
(5-aminooxalyl-7-benzyl-6-ethyl-2-phenoxymethylpyrrolo[1,2-b]pyridazine-4-yloxy) acetic acid,
Methyl[5-aminooxalyl-6-ethyl-2-methyl-7-(2-phenylbenzyl)pyrrolo[1,2-b]pyridazine-4-yloxy]acetate,
Ethyl [5-aminooxalyl-6-ethyl-2-methyl-7-(2-phenylbenzyl)pyrrolo[1,2-b]pyridazine-4-yloxy]acetate,
2-(Morpholine-4-yl)ethyl 5 -aminooxalyl-6-ethyl-2-methyl-7-(2-phenylbenzyl)pyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
Sodium[5-aminooxalyl-6-ethyl-2-methyl-7-(2-phenylbenzyl)pyrrolo[1,2-b]pyridazine-4-yloxy]acetate,
(5-aminooxalyl-6-ethyl-2-methyl-7-(2-phenylbenzyl)pyrrolo[1,2-b]pyridazine-4-yloxy)acetic acid,
Methyl(5-aminooxalyl-7-benzyl-6-methyl-2-propylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
Ethyl(5-aminooxalyl-7-benzyl-6-methyl-2-propylpyrrolo [1,2-b]pyridazine-4-yloxy)acetate,
2-(Morpholine-4-yl)ethyl 5-aminooxalyl-7-benzyl-6-methyl-2-propylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
Sodium (5-aminooxalyl-7-benzyl-6-methyl-2-propylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate, and
(5-aminooxalyl-7-benzyl-6-methyl-2-propylpyrrolo [1,2-b]pyridazine-4-yloxy) acetic acid,
and the prodrugs thereof; or their pharmaceutically acceptable salts; their parent acids; or their solvates.
xv) A pharmaceutical composition containing as active ingredient a compound as described in any one of i) to xiv).
xvi) A pharmaceutical composition as described in xv), which is for inhibiting sPLA2.
xvii) A pharmaceutical composition as described in xv), which is for treatment or prevention of Inflammatory Diseases.
xviii) A method of inhibiting sPLA2 mediated release of fatty acid which comprises contacting sPLA2 with a therapeutically effective amount of a pyrrolo[1,2-b]pyridazine compound as described in i).
xix) A method of treating a mammal, including a human, to alleviate the pathological effects of Inflammatory Diseases; wherein the method comprises administration to said mammal of a pyrrolo[1,2-b]pyridazine compound as described in i).
xx) A compound as described in i) or a pharmaceutical formulation containing an effective amount of a pyrrolo[1,2-b]pyridazine compound as described in i) for use in treatment of Inflammatory Diseases.
xxi) A compound as described in i) or a pharmaceutical formulation containing an effective amount of a pyrrolo[1,2-b]pyridazine compound as described in i) for use as an inhibitor for inhibiting sPLA2 mediated release of fatty acid.
xxii) A pyrrolo[1,2-b]pyridazine sPLA2 inhibitor substantially as hereinbefore described with reference to any of the Examples.
xxiii) A compound represented by the formula (XII): 
wherein R7 is xe2x80x94(CH2)mxe2x80x94R12 wherein m is an integer from 1 to 6, and R12 is (d) a group represented by the formula: 
wherein a, c, e, n, q, and t are independently an integer from 0 to 2, R13 and R14 are independently selected from a halogen, C1 to C10 alkyl, C1 to C10 alkyloxy, C1 to C10 alkylthio, aryl, heteroaryl, and C1 to C10 haloalkyl, a is an oxygen atom or a sulfur atom, L5 is xe2x80x94(CH2)vxe2x80x94, xe2x80x94Cxe2x95x90Cxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94Oxe2x80x94, or xe2x80x94Sxe2x80x94, v is an integer from 0 to 2, xcex2 is xe2x80x94CH2xe2x80x94 or xe2x80x94(CH2)2xe2x80x94, xcex3 is an oxygen atom or a sulfur atom, b is an integer from 0 to 3, d is an integer from 0 to 4, f, p, and w are independently an integer from 0 to 5, g is an integer from 0 to 2, r is an integer from 0 to 7, and u is an integer from 0 to 4, or is (e) a member of (d) substituted with at least one substituent selected from the group consisting of C1 to C6 alkyl, C1 to C6 alkyloxy, C1 to C6 haloalkyloxy, C1 to C6 haloalkyl, aryl, and a halogen; and
R1 is C1 to C3 alkyl, C2 to C3 alkenyl, C3 to C4 cycloalkyl, C3 to C4 cycloalkenyl, C1 to C2 haloalkyl, C1 to C3 alkyloxy, or C1 to C3 alkylthio.
In the present specification, the term xe2x80x9calkylxe2x80x9d employed alone or in combination with other terms means a straight- or branched chain monovalent hydrocarbon group having a specified number of carbon atoms. An example of the alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decanyl, n-undecanyl, n-dodecanyl, n-tridecanyl, n-tetradecanyl, n-pentadecanyl, n-hexadecanyl, n-heptadecanyl, n-octadecanyl, n-nonadecanyl, n-eicosanyl and the like.
The term xe2x80x9calkenylxe2x80x9d employed alone or in combination with other terms in the present specification means a straight- or branched chain monovalent hydrocarbon group having a specified number of carbon atoms and at least one double bond. An example of the alkenyl includes vinyl, allyl, propenyl, crotonyl, isopentenyl, a variety of butenyl isomers and the like.
The term xe2x80x9calkynylxe2x80x9d used in the present specification means a straight or branched chain monovalent hydrocarbon group having a specified number of carbon atoms and at least one triple bond. The alkynyl may contain (a) double bond(s). An example of the alkynyl includes ethynyl, propynyl, 6-heptynyl, 7-octynyl, 8-nonynyl and the like.
The term xe2x80x9ccarbocyclic groupxe2x80x9d used in the present specification means a group derived from a saturated or unsaturated, substituted or unsubstituted 5 to 14 membered, preferably 5 to 10 membered, and more preferably 5 to 7 membered organic nucleus whose ring forming atoms (other than hydrogen atoms) are solely carbon atoms. A group containing two to three of the carbocyclic group is also included in the above stated group. An example of typical carbocyclic groups includes (f) cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl); cycloalkenyl (such as cyclobutylenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooptenyl); phenyl, spiro[5,5]undecanyl, naphthyl, norbornyl, bicycloheptadienyl, tolyl, xylyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl, phenylcyclohexenyl, acenaphthyl, anthoryl, biphenylyl, bibenzylyl, and a phenylalkylphenyl derivative represented by the formula: 
wherein x is an integer from 1 to 8.
The term xe2x80x9cspiro[5,5]undecanylxe2x80x9d refers to the group represented by the formula: 
Phenyl, cyclohexyl or the like is preferred as a carbocyclic groups in the R4 and R5.
The term xe2x80x9cheterocyclic groupxe2x80x9d used in the present specification means a group derived from monocyclic or polycyclic, saturated or unsaturated, substituted or unsubstituted heterocyclic nucleus having 5 to 14 ring atoms and containing 1 to 3 hetero atoms selected from the group consisting of nitrogen atom, oxygen atom, and sulfur atom. An example of the heterocyclic group includes pyridyl, pyrrolyl, pyrrolidinyl, piperidinyl, furyl, benzofuryl, thienyl, benzothienyl, pyrazolyl, imidazolyl, phenylimidazolyl, triazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, indolyl, carbazolyl, norharmanyl, azaindolyl, benzofuranyl, dibenzofuranyl, dibenzothiophenyl, indazolyl, imidazo[1,2-a]pyridinyl, benzotriazolyl, anthranilyl, 1,2-benzisoxazolyl, benzoxazolyl, benzothiazolyl, purinyl, puridinyl, dipyridinyl, phenylpyridinyl, benzylpyridinyl, pyrimidinyl, phenylpyrimidinyl, pyrazinyl, 1,3,5-triazinyl, quinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, morpholino, thiomorpholino, homopiperazinyl, tetrahydrofuranyl, tetrahydropyranyl, oxacanyl, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,4-thioxanyl, azetidinyl, hexamethyleneiminium, heptamethyleneiminium, piperazinyl and the like.
Furyl, thienyl or the like is preferred as a heterocyclic group in the R4 and R5.
Preferred carbocyclic and heterocyclic groups in R1 are (g) a group represented by the formula: 
wherein R13 and R14 are independently selected from a halogen, C1 to C10 alkyl, C1 to C10 alkyloxy, C1 to C10 alkylthio, aryl, heteroaryl, and C1 to C10 haloalkyl, xcex1 is an oxygen atom or a sulfur atom, L5 is xe2x80x94(CH2)vxe2x80x94, xe2x80x94Cxe2x95x90Cxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94Oxe2x80x94, or xe2x80x94Sxe2x80x94, v is an integer from 0 to 2; xcex2 is xe2x80x94CH2xe2x80x94 or xe2x80x94(CH2)2xe2x80x94; xcex3 is an oxygen atom or a sulfur atom; b is an integer from 0 to 3, d is an integer from 0 to 4; f, p, and w are an integer from 0 to 5; r is an integer from 0 to 7, and u is an integer from 0 to 4. When the above b, d, f, p, r, u, and/or w are 2 or more, a plural number of R13 or R14 may be different from one another. When R13 is a substituent on the naphthyl group, the substituent may be substituted at any arbitrary position on the naphthyl group. A more preferable example includes (h) a group represented by the formula: 
wherein R13, R14, xcex1, xcex2, and xcex3 are the same as defined above, L6 is xe2x80x94CH2xe2x80x94, xe2x80x94Cxe2x95x90Cxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94Oxe2x80x94, or xe2x80x94Sxe2x80x94, and y is 0 or 1. When R13 is a substituent on the naphthyl group, the substituent may be substituted at any arbitrary position on the naphthyl group.
The xe2x80x9cpyrrolo[1,2-b]pyridazine nucleusxe2x80x9d is represented by the following structural formula together its numerical ring position for substituent placement: 
The term xe2x80x9cnon-interfering substituentxe2x80x9d in the present specification means C1 to C8 alkyl, C2 to C8 alkenyl, C2 to C8 alkynyl, C7 to C12 aralkyl (such as benzyl and phenethyl), C7 to C12 alkaryl, C2 to C8 alkenyloxy, C2 to C8 alkynyloxy, C3 to C8 cycloalkyl, C3 to C8 cycloalkenyl, phenyl, tolyl, xylyl, biphenylyl, C1 to C8 alkyloxy, C2 to C12 alkyloxyalkyl (such as methyloxymethyl, ethyloxymethyl, methyloxyethyl, and ethyloxyethyl), C2 to C12 alkyloxyalkyloxy (such as methyloxymethyloxy and methyloxyethyloxy), C2 to C12 alkylcarbonyl (such as methycarbonyl and ethylcarbonyl), C2 to C12 alkycarbonylamino (such as methylcarbonylamino and ethylcarbonylamino), C2 to C12 alkyloxyamino (such as methyloxyamino and ethyloxyamino), C2 to C12 alkyloxyaminocarbonyl (such as methyloxyaminocarbonyl and ethyloxyaminocarbonyl), C1 to C12 alkylamino (such as methylamino, ethylamino, dimethylamino, and ethylmethylamino), C1 to C6 alkylthio, C2 to C12 alkylthiocarbonyl (such as methylthiocarbonyl and ethyltiocarbonyl), C1 to C8 alkylsulfinyl (such as methylsulfinyl and ethylsulfinyl), C1 to C8 alkylsulfonyl (such as methylsulfonyl and ethylsulfonyl), C2 to c8 haloalkyloxy (such as 2-chloroethyloxy and 2-bromoethyloxy), C1 to C8 haloalkysulfonyl (such as chloromethylsulfonyl and bromomethylsulfonyl), C2 to C8 haloalkyl, C1 to C8 hydroxyalkyl (such as hydroxymethyl and hydroxyethyl), xe2x80x94C(O)O(C1 to C8 alkyl) (such as methyloxycarbonyl and ethyloxycarbonyl, xe2x80x94(CH2)zxe2x80x94Oxe2x80x94(C1 to C8 alkyl), benzyloxy, aryloxy (such as phenyloxy), arylthio (such as phenylthio), xe2x80x94(CONHSO2R25), xe2x80x94CHO, amino, amidino, halogen, carbamyl, carboxyl, carbalkyloxy, xe2x80x94(CH2)zxe2x80x94COOH (such as carboxymethyl, carboxyethyl, and carboxypropyl), cyano, cyanoguanidino, guanidino, hydrazido, hydroxy, hydroxyamino, nitro, phosphono, xe2x80x94SO3H, carbocyclic groups, heterocyclic groups wherein z is an integer from 1 to 8 and R25 is C1 to C6 alkyl or aryl. These groups may be substituted by at least one substituent selected from the group consisting of C1 to C6 alkyl, C1 to C6 alkyloxy, C2 to C6 haloalkyloxy, C1 to C6 haloalkyl, and halogens.
Preferable are halogens, C1 to C6 alkyl, C1 to C6 alkyloxy, C1 to C6 alkylthio, and C1 to C6 haloalkyl as the xe2x80x9cnon-interfering substituentxe2x80x9d in the R1. More preferable are halogens, C1 to C3 alkyl, C1 to C3 alkyloxy, C1 to C3 alkylthio, and C1 to C3 haloalkyl.
Preferable are (i) C1 to C6 alkyl, aralkyl, C1 to C6 alkyloxy, C1 to C6 alkylthio, C1 to C6 hydroxyalkyl, C2 to C6 haloalkyloxy, halogens, carboxy, C1 to C6 alkyloxycarbonyl, aryloxy, arylthio, carbocyclic groups, and heterocyclic groups as the xe2x80x9cnon-interfering substituentsxe2x80x9d in the R4, R5, R10, and R11. More preferable are (j) C1 to C6 alkyl, aralkyl, carboxy, C1 to C6 hydroxyalkyl, phenyl, and C1 to C6 alkyloxycarbonyl.
The term xe2x80x9chalogenxe2x80x9d in the present specification means fluorine, chlorine, bromine, and iodine.
The term xe2x80x9ccycloalkylxe2x80x9d in the present specification means a monovalent cyclic hydrocarbon group having a specified number of carbon atoms. An example of the cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
The term xe2x80x9ccycloalkenylxe2x80x9d in the present specification means a monovalent cyclic hydrocarbon group having a specified number of carbon atoms and at least one double bond(s). An example of the cycloalkenyl includes 1-cyclopropenyl, 2-cyclopropenyl, 1-cyclobutenyl, 2-cyclobutenyl and the like.
In the present specification, an example of xe2x80x9calkyloxyxe2x80x9d includes methyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy, n-pentyloxy, n-hexyloxy and the like.
In the present specification, an example of xe2x80x9calkylthioxe2x80x9d includes methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, n-pentylthio, n-hexylthio and the like.
The term xe2x80x9cacidic groupxe2x80x9d in the present specification means an organic group functioning as a proton donor capable of hydrogen bonding when attached to a pyrrolo[1,2-b]pyridazine nucleus through a suitable linking atom (hereinafter defined as xe2x80x9cacid linkerxe2x80x9d). An example of the acidic group includes (k) a group represented by the formula: 
wherein R18 is hydrogen atom, a metal, or C1 to C10 alkyl and each R19is independently hydrogen atom or C1 to C10 alkyl. Preferable is (1) xe2x80x94COOH, xe2x80x94SO3H, or P(O)(OH)2. More preferable is (m)xe2x80x94COOH.
The term xe2x80x9cacid linkerxe2x80x9d in the present specification means a divalent linking group represented by a symbol xe2x80x94(L2)xe2x80x94, and it functions to join 4-position of pyrrolo[1,2-b]pyridazine nucleus to an xe2x80x9cacidic groupxe2x80x9d in the general relationship. An example of it includes (n) a group represented by the formula: 
M is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94N(R24)xe2x80x94, or xe2x80x94Sxe2x80x94, and R16 and R17 are independently hydrogen atom, C1 to C10 alkyl, aryl, aralkyl, carboxy, or halogens. Preferable are (o) xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94Sxe2x80x94CH2xe2x80x94, xe2x80x94N(R24)xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94CH(CH3)xe2x80x94, or xe2x80x94Oxe2x80x94CH((CH2)2Ph)xe2x80x94 wherein R24 is hydrogen atom or C1 to C6 alkyl and Ph is phenyl. More preferable is (p) xe2x80x94Oxe2x80x94CH2xe2x80x94 or xe2x80x94Sxe2x80x94CH2xe2x80x94.
In the present specification, the term xe2x80x9cacid linker lengthxe2x80x9d means the number of atoms (except for hydrogen atoms) in the shortest chain of a linking group xe2x80x94(L2)xe2x80x94 which connects 4-position in pyrrolo[1,2-b]pyridazine nucleus with the xe2x80x9cacidic groupxe2x80x9d. The presence of a carbocyclic ring in (L2 counts as the number of atoms approximately equivalent to the calculated diameter of the carbocyclic ring. Thus, a benzene and cyclohexane ring in the acid linker counts as two atoms in culculating the length of xe2x80x94(L2)xe2x80x94. preferable length is 2 to 3.
A symbol k in the formula (IV) is preferably 1.
The term xe2x80x9chaloalkylxe2x80x9d in the present specification means the above described xe2x80x9calkylxe2x80x9d substituted with the above described xe2x80x9chalogenxe2x80x9d at arbitrary position(s). An example of the haloalkyl includes chloromethyl, trifluoromethyl, 2-chloromethyl, 2-bromomethyl and the like.
The term xe2x80x9chydroxyalkylxe2x80x9d in the present specification means the aforementioned xe2x80x9calkylxe2x80x9d substituted with hydroxy at arbitrary position(s). An example of the hydroxyalkyl includes hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl and the like. In this case, hydroxymethyl is preferable.
In the present specification, the term xe2x80x9chaloalkylxe2x80x9d in xe2x80x9chaloalkyloxyxe2x80x9d is the same as defined above. An example of it includes 2-chloroethyloxy, 2,2,2-trifluoroethyloxy, 2-chloroethyloxy and the like.
The term xe2x80x9carylxe2x80x9d in the present specification means a monocyclic or condensed cyclic aromatic hydrocarbon. An example of the aryl includes phenyl, 1 -naphthyl, 2-naphthyl, anthryl and the like. Particularly, phenyl and 1 -naphthyl are preferred. Such xe2x80x9carylxe2x80x9d is optionally substituted with C1 to C6 alkyl, hydroxy, C1 to C3 alkyloxy, halogen, nitro, substituted or unsubstituted amino, cyano, C1 to C3 haloalkyl, and the like at one or more position(s).
The term xe2x80x9caralkylxe2x80x9d in the present specification means a group wherein the aforementioned xe2x80x9calklxe2x80x9d is substituted with the above-mentioned xe2x80x9carylxe2x80x9d. Such aryl may have a bond at any substitutable position. An example of it includes benzyl, phenethyl, phenylpropyl (such as 3 -phenylpropyl), naphthylmethyl (such as 1-naphthylmethyl) and the like.
The term xe2x80x9cgroup containing 1 to 4 non-hydrogen atomsxe2x80x9d refers to relatively small groups which form substituents at the 6 position of the pyrrolo[1,2-b]pyridazine nucleus, said groups may contain non-hydrogen atoms alone, or non-hydrogen atoms plus hydrogen atoms as required to satisfy the unsubstituted valence of the non-hydrogen atoms, for example; (ii) groups absent hydrogen which contain no more than 4 non-hydrogen atoms such as xe2x80x94CF3, xe2x80x94Cl, xe2x80x94Br, xe2x80x94NO2, xe2x80x94CN, xe2x80x94SO3; and (iii) groups having hydrogen atoms which contain less than 4 non-hydrogen atoms such as xe2x80x94CH3, xe2x80x94C2H5, xe2x80x94CHxe2x95x90CH2, xe2x80x94CH(CH3)2, and cyclopropyl.
An example of the xe2x80x9calkyloxycarbonylxe2x80x9d in the present specification includes methyloxycarbonyl, ethyloxycarbonyl, n-propyloxycarbonyl and the like.
The term xe2x80x9csubstituted aminoxe2x80x9d in the present specification includes amino substituted with C1 to C6 alkyl, aralkl, C1 to C6 alkylcarbonyl, C1 to C6 alkyloxycarbonyl, and the like at one or two position(s).
Preferred embodiments of the R7 of the formula (XXII) are C5 to C8 cycloalkylmethyl and phenylmethyl which is optionally substituted with halogen, C1 to C6 alkyl, aryl, alkyloxy, or aryloxy.
Preferable is C1 to C6 alkyl as the R8 of the formula (XXII).
A group of preferable substituents as the R1 to R5 and the RA of the compound represented by the formula (I) will be shown in items (A) to (W). Items (f) to (m) are the same group as described above.
As the R1, (A): xe2x80x94(L1)xe2x80x94R6, (B): xe2x80x94(CH2)1-2-(f), (C): xe2x80x94(CH2)1-2-(g), and (D): xe2x80x94(CH2)1-2-(h) are preferred.
As the R2, (E): hydrogen atom, halogen, C1 to C3 alkyl, C3 to C4 cycloalkyl, or C1 to C3 alkyloxy; and (F): C1 to C3 alkyl or C3 to C4 cycloalkyl are preferred.
As the RA, (G): xe2x80x94C(xe2x95x90O)xe2x80x94C(xe2x95x90O)xe2x80x94NH2, xe2x80x94CH2C(xe2x95x90O)xe2x80x94NH2, or xe2x80x94CH2C(xe2x95x90O)xe2x80x94NHNH2; and (H): xe2x80x94C(xe2x95x90O)xe2x80x94C(xe2x95x90O)xe2x80x94NH2 are preferred.
As the R3, (I): -(n)-(k), (J): -(n)-(l), (K): -(n)-(m), (L): -(o)-(k), (M): -(o)-(l), (N): -(o)-(m), (O): -(p)-(k), (P): -(p)-(l), and (Q): -(p)-(m) are preferred.
As the R4, (R): hydrogen atom or non-interfering substituent, (S): hydrogen atom or (i), and (T): hydrogen atom or (j) are preferred.
As the R5, (U): hydrogen atom or (i), (V): hydrogen atom or (j), and (W): hydrogen atom are preferred.
A preferred group of compounds represented by the formula (I) is shown below.
(R1,R2,RA,R4,R5)=(A,E,G,R,U), (A,E,G,R,V), (A,E,G,R,W), (A,E,G,S,U), (A,E,G,S,V), (A,E,G,S,W), (A,E,G,T,U), (A,E,G,T,V), (A,E,G,T,W), (A,E,H,R,U), (A,E,H,R,V), (A,E,H,R,W), (A,E,H,S,U), (A,E,H,S,V), (A,E,H,S,W), (A,E,H,T,U), (A,E,H,T,V), (A,E,H,T,W), (A,F,G,R,U), (A,F,G,R,V), (A,F,G,R,W), (A,F,G,S,U), (A,F,G,S,V), (A,F,G,S,W), (A,F,G,T,U), (A,F,G,T,V), (A,F,G,T,W), (A,F,H,U), (A,F,H,R,V), (A,F,H,R,W), (A,F,H,S,U), (A,F,H,S,V), (A,F,H,S,W), (A,F,H,T,U), (A,F,H,T,V), (A,F,H,T,W), (B,E,G,R,U), (B,E,G,R,V), (B,E,G,R,W), (B,E,G,S,U), (B,E,G,S,V), (B,E,G,S,W), (B,E,G,T,U), (B,E,G,T,V), (B,E,G,T,W), (B,E,H,R,U), (B,E,H,R,V), (B,E,H,R,W), (B,E,H,S,U), (B,E,H,S,V), (B,E,H,S,W), (B,E,H,T,U), (B,E,H,T,V), (B,E,H,W), (B,F,G,R,U), (B,F,G,R,V), (B,F,G,R,W), (B,F,G,S,U), (B,F,G,S,V), (B,F,G,S,W), (B,F,G,T,U), (B,F,G,T,V), (B,F,G,T,W), (B,F,H,R,U), (B,F,H,R,V), (B,F,H,R,W), (B,F,KS,U), (B,F,H,S,V), (B,F,H,S,W), (B,F,H,T,U), (B,F,H,T,V), (B,F,H,T,W), (C,E,G,R,U), (C,E,G,R,V), (C,E,G,R,W), (C,E,G,S,U), (C,E,G,S,V), (C,E,G,S,W), (C,E,G,T,U), (C,E,G,T,V), (C,E,G,T,W), (C,E,H,R,U), (C,E,H,R,V), (C,E,H,R,W), (C,E,H,S,U), (C,E,H,S,V), (C,E,H,S,W), (C,E,H,T,U), (C,E,H,T,V), (C,E,H,T,W), (C,F,G,R,U), (C,F,G,R,V), (C,F,G,R,W), (C,F,G,S,U), (C,F,G,S,V), (C,F,G,S,W), (C,F,G,T,U), (C,F,G,T,V), (C,F,G,T,W), (C,F,H,R,U), (C,F,H,R,V), (C,F,H,R,W), (C,F,H,S,U), (C,F,H,S,V), (C,F,H,S,W), (C,F,H,T,U), (C,F,H,T,V), (C,F,H,T,W), (D,E,G,R,U), (D,E,G,R,V), (D,E,G,R,W), (D,E,G,S,U), (D,E,G,S,V), (D,E,G,S,W), (D,E,G,T,U), (D,E,G,T,V), (D,E,G,T,W), (D,E,H,R,U), (D,E,H,R,V), (D,E,H,R,W), (D,E,H,S,U), (D,E,H,S,V), (D,E,H,S,W), (D,E,H,T,U), (D,E,H,T,V), (D,E,H,T,W), (D,F,G,R,U), (D,F,G,R,V), (D,F,G,R,W), (D,F,G,S,U), (D,F,G,S,V), (D,F,G,S,W), (D,F,G,T,U), (D,F,G,T,V), (D,F,G,T,W), (D,F,H,R,U), (D,F,H,R,V), (D,F,H,R,W), (D,F,H,S,U), (D,F,H,S,V), (D,F,H,S,W), (D,F,H,T,U), (D,F,H,T,V), and (D,F,H,T,W).
Preferred embodiments of this invention are compounds wherein R3 is any one of (I) to (Q) and (R1,R2,RA,R4,R5) is any one of the above combinations.
The term, xe2x80x9cInflammatory Diseasesxe2x80x9d refers to diseases such as inflammatory bowel disease, sepsis, septic shock, adult respiratory distress syndrome, pancreatitis, trauma-induced shock, bronchial asthma, allergic rhinitis, rheumatoid arthritis, chronic rheumatism, arterial sclerosis, cereberal hemorrhage, cerebral infarction, cardiac failure, cardiac infarction, psoriasis, cystic fibrosis, stroke, acute bronchitis, chronic bronchitis, acute bronchiolitis, chronic bronchiolitis, osteoarthritis, gout, spondylarthropathris, ankylosing spondylitis, Reiter""s syndrome, psoriatic arthropathy, enterapathric spondylitis, Juvenile arthropathy or juvenile ankylosing spondylitis, Reactive arthropathy, infectious or post-infectious arthritis, gonoccocal arthritis, tuberculous arthritis, viral arthritis, fungal arthritis, syphilitic arthritis, Lyme disease, arthritis associated with xe2x80x9cvasculitic syndromesxe2x80x9d, polyarteritis nodosa, hypersensitivity vasculitis, Luegenec""s granulomatosis, polymyalgin rheumatica, joint cell arteritis, calcium crystal deposition arthropathris, pseudo gout, non-articular rheumatism, bursitis, tenosynomitis, epicondylitis (tennis elbow), carpal tunnel syndrome, repetitive use injury (typing), miscellaneous forms of arthritis, neuropathic joint disease (charco and joint), hemarthrosis (hemarthrosic), Henoch-Schonlein Purpura, hypertrophic osteoarthropathy, multicentric reticulohistiocytosis, arthritis associated with certain diseases, surcoilosis, hemochromatosis, sickle cell disease and other hemoglobinopathries, hyperlipoproteineimia, hypogammaglobulinemia, hyperparathyroidism, acromegaly, familial Mediterranean fever, Behat""s Disease, systemic lupus erythrematosis, or relapsing polychondritis and related diseases which comprises administering to a mammal in need of such treatment a therapeutically effective amount of the compound of formula I in an amount sufficient to inhibit sPLA2 mediated release of fatty acid and to thereby inhibit or prevent the arachidonic acid cascade and its deleterious products.
The terms, xe2x80x9cmammalxe2x80x9d and xe2x80x9cmammalianxe2x80x9d include human.
The term xe2x80x9csolvatexe2x80x9d includes, for example, solvates with organic solvents, hydrates, and the like.
The compounds of the invention represented by the formula (I) can be synthesized in accordance with the following method A. The compound (XV) in the method A can be also synthesized in accordance with the following method B.
(Method A) 
wherein R1, R2, R4, R5, X, and Y are as defined above; R26 is an acidic group.
(Step 1)
To a solution of the compound (VI) which is commercially available or is synthesized in accordance with well-known method in a solvent such as tetrahydrofuran, diethyl ether, and ethylene glycol dimethyl ether is added a base such as lithium diisopropyl amide and n-butyllithium at xe2x88x9278xc2x0 C., to xe2x88x9220xc2x0 C., preferably xe2x88x9278xc2x0 C. to xe2x88x9260xc2x0 C. To the reaction mixture is added alkenyl halide such as allyl bromide and allyl chloride at the same temperature and the resulting mixture is stirred for 1 to 24 h, preferably 1 to 8 h. After the reaction mixture is subjected to a usual work-up, the compound (VII) can be obtained (see J. Chem. Soc. Parkin. Trans.1, 1987, 1986).
(Step 2)
To a solution of the compound (VII) in a solvent such as tetrahydrofuran, diethyl ether, and ethylene glycol dimethyl ether is added Grignard reagent (R1MgHal: Hal is a halogen) at xe2x88x9220xc2x0 C. to 0xc2x0 C., preferably xe2x88x9215xc2x0 C. to xe2x88x9210xc2x0 C. and the resulting mixture is stirred for 1 to 15 h, preferably 1 to 8 h at xe2x88x9220xc2x0 C. to 30xc2x0 C., preferably 0xc2x0 C. to 25xc2x0 C. After the reaction mixture is subjected to a usual work-up, the compound (VIII) can be obtained (see Synthesis, 996, 1988).
(Step 3)
The present step includes ozone-oxidation of the double bond. A solution of the compound (VIII) in a solvent such as dichloromethane, ethyl acetate, and methanol is treated with ozone at xe2x88x9278xc2x0 C. to 0xc2x0 C., preferably xe2x88x9278xc2x0 C. to xe2x88x9260xc2x0 C. Without isolating the ozonide, the mixture is treated with a reducing agent such as dimethyl sulfide, triphenylphosphine, triethoxyphosphine, and zinc-acetic acid or hydrogen to give the aldehyde derivative (IX).
(Step 4)
To a solution of the compound (IX) in a solvent such as dioxane, tetrahydrofuran, and diethyl ether are added the compound (X) and an acid such as hydrochloric acid, sulfuric acid, and acetic acid. The resulting mixture is stirred for 0.5 to 3 h at 50xc2x0 C. to 100xc2x0 C. to give the pyrrole derivative (XI) which is protected by phthalimide at N-position (Chem. Ber., 102, 3268, 1969).
(Step 5)
The present step is the one for deprotecting the phthalimide group of the compound (XI). This step may be carried out in accordance with a usual deprotecting method as described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley and Sons). For example, to a solution of the compound (XI) in an alcohol solvent such as ethanol is added hydrazine and the resulting mixture is stirred for 0.5 to 3 h at 50xc2x0 C. to 100xc2x0 C. to give the amino derivative (XII).
(Step 6)
The present step is the one for alkylating the amino group. The compound (XII) and the compound (XIII) are reacted for 10 to 60 min at 100xc2x0 C. to 150xc2x0 C. to give the compound (XIV) (see J. Heterocyclic Chem., 31, 409, 1994).
(Step 7)
The present step is the one for constructing pyrrolo[1,2-b]pyridazine ring. The compound (XIV) is dissolved in a solvent such as Dowtherm-A and SAS-296 and the mixture is stirred for 1 to 8 h at 150xc2x0 C. to 250xc2x0 C. to give the pyrrolo[1,2-b]pyridazine derivative (XV) (see J. Heterocyclic Chem., 31, 409, 1994). The hydroxy group at 4-position is converted into halogen by the usual method, then the halogen is may be converted into a thiol group or the like.
(Step 8)
To a solution of the compound (XV) in a solution such as tetrahydrofuran and dimethylformamide are added a base such as potassium carbonate and sodium hydride and R26-Hal (Hal is halogen) and the resulting mixture is stirred for 1 to 15 h at 0xc2x0 C. to 100xc2x0 C., preferably 20 to 40xc2x0 C. to give the compound (XVI).
(Step 9)
The present step is the one for introducing a substituent to 5-position. The compound (XVI) is dissolved in a solvent such as 1,2-dichloroethane, tetrahydrofuran, and Hal-C(xe2x95x90X)xe2x80x94C(xe2x95x90X)-Hal (for example, oxalyl chloride) and a base such as N-methylmorpholine, triethylamine are added to the solution, and the mixture is stirred for 1 to 10 h, preferably 3 to 6 h at 30xc2x0 C. to 70xc2x0 C., preferably 40xc2x0 C. to 60xc2x0 C. The reaction mixture is poured into cold aqueous ammonia, and the resulting mixture is stirred for 5 to 30 minutes, preferably 10 to 20 minutes. After the reaction mixture is subjected to an ordinary work-up, the compound (XVII) can be obtained.
(Method B) 
wherein R1, R2, R4, and R5 are as defined above, R27 is C1 to C3 alkyl, R28 is lower alkyl R28 with the adjacent oxygen may form a 1,3-dioxolane ring, and R29 is a phthalimido or NHCO2Et.
(Step 1)
To a solution of the compound (XVIII) in a solvent such as dimethylformamide are added a halogenated alkyl derivative such as bromoacetaldehyde ethyleneacetal and a base such as potassium carbonate, potassium t-butoxide, and sodium hydride and the resulting mixture is stirred for 3 to 80 h, preferably 5 to 7 h at room temperature to 180xc2x0 C., preferably 20 to 150xc2x0 C. to give the compound (XIX).
(Step 2)
To a solution of the compound (XIX) in a solvent such as dimethylsulfoxide is added a reagent such as potassium acetate and sodium acetate and the resulting mixture is stirred for 1 to 20 h, preferably 3 to 15 h at 20xc2x0 C. to 200xc2x0 C., preferably 100xc2x0 C. to 180xc2x0 C. to give the compound (XX).
(Step 3)
To a solution of Grignard reagent (R1MgHal, Hal is halogen) or R1Li in a solvent such as ether, tetrahydrofuran, and dimethoxyethane is added a solution of the compound (XX) in ether, tetrahydrofuran, and dimethoxyethane and the resulting mixture is stirred for 1 to 48 h, preferably 2 to 24 h at 0xc2x0 C. to 70xc2x0 C., preferably 20 to 60xc2x0 C. to give the compound (XXI).
(Step 4)
To a solution of the compound (XXI) in a solvent such as ethanol, methanol, dioxane, and tetrahydrofuran are added N-aminophthalimide (compound (X)) or ethyl carbazate (compound (XXII)) and an acid such as trifluoroacetic acid, hydrochloric acid, and sulfuric acid and the resulting mixture is stirred for 5 min to 2 h, preferably 10 min to 1 h at 20xc2x0 C. to 120xc2x0 C., preferably 50 to 100xc2x0 C. to give the compound (XXIII).
(Step 5)
The present step may be carried out in accordance with the same procedure as that of the method Axe2x80x94step 5.
To a solution of the compound (XIIxe2x80x2) in a solvent such as chloroform, dichloroethane, tetrahydrofuran, and toluene are added xcex2-ketoester such as acetoacetic acid methylester and an acid catalyst such as p-toluenesulfonic acid, methanesulfonic acid, hydrochloric acid, trifluoroacetic acid and the resulting mixture is stirred for 1 to 20 h, preferably 3 to 15 h to give the compound (XV). The generated water in situ is dehydrated by a Dean-Stark apparatus with molecular sieve 4A or the like.
(Method C) 
wherein R1, R2, R4, R26, X, and Y are as defined above, Hal is halogen, R30 is xe2x80x94OR31, xe2x80x94SR31, xe2x80x94NHR31, xe2x80x94N(R31)2, xe2x80x94CN, xe2x80x94N3, or the like wherein R31 is independently alkyl, aryl, or the like.
(Step 1)
The compound (XVIxe2x80x2) is obtained in a manner similar to that described in the method Axe2x80x94step 8.
(Step 2)
The compound (XVIxe2x80x2) is dissolved in a solvent such as dimethylformamide, acetonitrile, acetone, dimethylsulfoxide, methanol, ethanol, isopropanol and to the solution is added a base as a dehydrohalogenating agent such as potassium carbonate, sodium carbonate, sodium hydrogencarbonate, sodium acetate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium t-butoxide. Then to the mixture is added a reagent such as R31OH, R31SH, R31NH2, (R31)2NH and the resulting mixture is stirred for 1 to 48 h preferably 1 to 24 h at xe2x88x9220xc2x0 C. to 100xc2x0 C., preferably 0xc2x0 C. to 80xc2x0 C. to give the compound (XXIV).
(Step 3)
The compound (XVIIxe2x80x2) is obtained in a manner similar to that described in the method Axe2x80x94step 9.
(Method D) 
wherein R1, R2,R4, R26, R30, X, Y, and Hal are as defined above.
(Step 1)
The compound (XXV) is obtained in a manner similar to that described in the method Axe2x80x94step 9.
The compound (XVIIxe2x80x2) is obtained in a manner similar to that described in the method Cxe2x80x94step 2.
Where a compound of the present invention has an acidic or basic functional group, a variety of salts each having higher water solubility and more physiologically suitable properties than those of the original compound can be formed. An example of typical pharmaceutically acceptable salts includes salts with alkali metal and alkaline earth metal such as lithium, sodium, potassium, magnesium, aluminum and the like, but it is to be noted that such pharmaceutically acceptable salts are not limited thereto. A salt is easily manufactured from a free acid by either treating an acid in a solution with a base, or allowing an acid to be in contact with an ion exchange resin. Addition salts of the compounds according to the present invention with relatively non-toxic inorganic bases and organic bases, for example, amine cation, ammonium, and quaternary ammonium derived from nitrogenous bases having a basicity sufficient for forming a salt of the compounds of the present invention are included in the definition of xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d. (e.g., S. M. Berge et al., xe2x80x9cPharmaceutical Salts,xe2x80x9d J. Phar. Sci., 66, 1-19 (1977)) Furthermore, basic groups of a compound according to the present invention are reacted with a suitable organic or inorganic acid to form salts such as acetates, benzenesulfonates, benzoates, bicarbonates, bisulfates, bitartarate, borates, bromides, camcyrates, carbonates, chlorides, clubranates, citrates, edetates, edicirates, estrates, ethylates, fluorides, fumarates, gluseptates, gluconates, glutamates, glycolialsanyrates, hexyliresorcinates, hydroxynaphthoates, iodides, isothionates, lactates, lactobionates, laurates, malates, malseates, manderates, mesylates, methylbromides, methylnitrates, methylsulfates, mucates, napcylates, nitrates, oleates, oxarates, palmitates, pantothenates, phosphates, polygalacturonates, salicirates, stearates, subacetates, sucinates, tanates, tartrates, tosylates, trifluoroacetates, trifluoromethanesulfonates, valerates and the like. In case of forming a hydrate, a questioned compound may be coordinated with a suitable number of water molecules.
In the case where a compound of the present invention has one or more of chiral center(s), it may exist as an optically active member. Likewise, in the case where a compound contains alkenyl or alkenylene, there is a possibility of cis- and trans-isomers. Mixtures of R- and S-isomers as well as of cis- and trans-isomers, and mixtures of R- and S-isomers containing racemic mixture are included in the scope of the present invention. Asymmetric carbon atom may exist also in a substituent such as alkyl group. All such isomers are included in the present invention together with these mixtures. In the case where a specified streoisomer is desired, either it is manufactured by applying a manner which has been well known by those skilled in the art wherein a starting material having an asymmetrical center which has been previously separated is subjected to stereospecific reaction to the starting material, or it is manufactured by preparing a mixture of stereoisomers, and thereafter separating the mixture in accordance with a well-known manner.
Prodrug is a derivative of the compound having a group which can be decomposed chemically or metabolically, and such prodrug is a compound according to the present invention which becomes pharmaceutically active by means of solvolysis or by placing the compound in vivo under a physiological condition. Although a derivative of the compounds according to the present invention exhibits activity in both forms of acid derivative and basic derivative, acid derivative is more advantageous in solubility, tissue affinity, and release control in mammal organism (Bungard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam, 1985). Ester prodrugs are well known (see, Silverman, Richard B, The Organic Chemistry of Drug Design and Drug Action, Chapter 8, New York, N.Y. Academic Press, ISBN 0-12-643730-0) and are a preferred prodrug form for the compounds of this invention and also for prodrugs used in the method of treating Inflammatory Disease as taught herein. For instance, prodrugs each containing an acid derivative such as an ester which is prepared by reacting a basal acid compound with a suitable alcohol, or an amide which is prepared by reacting a basal acid compound with a suitable amine are well known by those skilled in the art. Simple aliphatic or aromatic esters derived from acid groups contained in the compounds according to the present invention are preferable prodrugs. Particularly preferred esters as prodrugs are methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, tert-butyl ester, morpholinoethyl ester, and N,N-diethylglycolamido ester.
Methyl ester prodrugs may be prepared by reaction of the sodium salt of a compound of Formula (I) (in a solvent such as dimethylformamide) with iodo methane (available from Aldrich Chemical Co., Milwaukee, Wis. USA; Item No. 28,956-6).
Ethyl ester prodrugs may be prepared by reaction of the sodium salt of a compound of Formula (I) (in a solvent such as dimethylformamide) with iodo ethane (available from Aldrich Chemical Co., Milwaukee, Wis. USA; Item No. I-778-0).
N,N-diethylglycolamido ester prodrugs may be prepared by reaction of the sodium salt of a compound of Formula (I) (in a medium such as dimethylformamide) with 2-chloro-N,N-diethylacetamide (available from Aldrich Chemical Co., Milwaukee, Wis. USA; Item No. 25,099-6).
Morpholinylethyl ester prodrugs may be prepared by reaction of the sodium salt of a compound of Formula (I) (in a medium such as dimethylformamide) with 4-(2-chloroethyl)morpholine hydrochloride (available from Aldrich Chemical Co., Milwaukee, Wis. USA, Item No. C4,220-3).
Double ester such as (acyloxy)alkyl ester or ((alkyloxycarbonyl)oxy)alkyl ester type prodrugs may be optionally manufactured.
The term xe2x80x9cinhibitxe2x80x9d means that release of fatty acid started by sPLA2 decreases significantly by the compounds of the present invention from viewpoint of prevention and treatment of disease. The term xe2x80x9cpharmaceutically acceptablexe2x80x9d means that carriers, diluents, or additives are compatible with other ingredients in a formulation and are not harmful for recipients.
The compounds of the present invention exhibit sPLA2 inhibiting activity as per the description of the experimental examples which will be described hereinafter. Accordingly, when a curatively effective amount of the compounds represented by the formulae (I), (II), (III), and (IV), the prodrug derivatives thereof, or their pharmaceutically acceptable salts, or their solvates is administered to any of mammals (including human being), it functions effectively as a curative medicine for diseases of septic shock, adult respiratory distress syndrome, pancreatitis, injury, bronchial asthma, allergic rhinitis, chronic rheumatism, arterial sclerosis, cerebral hemorrhage, cerebral infarction, inflammatory colitis, mange, cardiac failure, cardiac infarction.
The compounds of the present invention may be administered to a patient through a variety of routes including oral, aerosol, rectal, percutaneous, subcutaneous, intravenous, intramuscular, and nasal routes. A formulation according to the present invention may be manufactured by combining (for example, admixing) a curatively effective amount of a compound of the present invention with a pharmaceutically acceptable carrier or diluent. The formulation of the present invention may be manufactured with the use of well-known and easily available ingredients in accordance with a known method.
In case of manufacturing a composition according to the present invention, either active ingredients are admixed with a carrier, or they are diluted with a carrier, or they are contained in a carrier in the form of capsule, sacheier, paper, or another container. In case of functioning a carrier as a diluent, the carrier is a solid, semi-solid, or liquid material which functions as a medium. Accordingly, a formulation according to the present invention may be produced in the form of tablet, pill, powder medicine, intraoral medicine, elixir agent, suspending agent, emulsifier, dissolving agent, syrup agent, aerosol agent (solid in liquid medium), and ointment. Such a formulation may contain up to 10% of an active compound. It is preferred to prepare a compound according to the present invention prior to administration.
Any suitable carrier which has been well known by those skilled in the art may be used for the formulation. In such formulation, a carrier is in the form of solid, liquid, or a mixture of solid and liquid. For instance, a compound of the present invention is dissolved into 4% dextrose/0.5% sodium citrate aqueous solution so as to be 2 mg/ml concentration for intravenous injection. Solid formulation includes powder, tablet, and capsule. Solid carrier consists of one or more of material(s) for serving also as fragrant, lubricant, dissolving agent, suspension, binder, tablet disintegrator, capsule. A tablet for oral administration contains a suitable excipient such as calcium carbonate, sodium carbonate, lactose, calcium phosphate and the like together with a disintegrator such as corn starch, alginic acid and the like and/or a binder such as gelatin, acacia and the like, and a lubricant such as magnesium stearate, stearic acid, talc and the like.
In a powder medicine, a carrier is a finely pulverized solid which is blended with finely pulverized active ingredients. In a tablet, active ingredients are admixed with a carrier having required binding power in a suitable ratio, and it is solidified in a desired shape and size. Powder medicine and tablet contain about 1 to about 99% by weight of the active ingredients being novel compounds according to the present invention. An example of suitable solid carriers includes magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methyl cellulose, sodium carboxymethylcellulose, low-melting wax, and cocoa butter.
An axenic liquid formulation contains suspending agent, emulsifier, syrup agent, and elixir agent. Active ingredients may be dissolved or suspended into a pharmaceutically acceptable carrier such as sterile water, a sterile organic solvent, a mixture thereof and the like. Active ingredients may be dissolved frequently into a suitable organic solvent such as propylene glycol aqueous solution. When finely pulverized active ingredients are dispersed into aqueous starch, sodium carboxylmethylcellulose solution, or suitable oil, the other compositions can be prepared.
A lyophilized preparation may be prepared by dissolving active ingredients in a solution such as water, if necessary, with a solubilizer such as citric acid, edetic acid, polyphosphoric acid and their salts and a stabilizer such as mannitol, xylitol, sorbitol, glucose, fructose, lactose and maltose and lyophilizing it.
The method of the invention for inhibiting sPLA2 mediated release of fatty acids comprises contacting mammalian sPLA2 with a therapeutically effective amount of a pyrrolo[1,2-b]pyridazine sPLA2 inhibitors (and formulation containing such inhibitors) as taught, supra.
Preferably compounds of the invention (per Formula (I) or (II) or (III) or (IV) or pharmaceutical formulations containing these compounds) are in unit dosage form for administration to a mammal. The unit dosage form can be a capsule or tablet itself, or the appropriate number of any of these. The quantity of Active ingredient in a unit dose of composition may be varied or adjusted from about 0.1 to about I 000 milligrams or more according to the particular treatment involved. It may be appreciated that it may be necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration.
The improved method of treatment for sepsis using the pyrrolo[1,2-b]pyridazine sPLA2 inhibitors (and formulation containing such inhibitors) may be practiced as follows:
The inhibitors of this invention are given by injection, either subcutaneously or into muscle tissue or by injection into a vein. Intravenous injection is the preferred mode of delivery to the mammal being treated and offers the advantage of a quick effect and rapid access into the circulation system, particularly in emergency situations.
It may be appreciated that it may be necessary to make routine variations to the dosage depending on the age and condition of the patient. The specific dose of a compound administered according to this invention to obtain therapeutic or prophylactic effects will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration and the condition being treated. Typical daily doses will contain a non-toxic Compound (I) dosage level of from about 0.01 mg/kg to about 50 mg/kg of body weight of an Active ingredient of this invention.
This invention is a method of treating or preventing Inflammatory diseased, (e.g., sepsis, rheumatoid arthritis, osteoarthritis, asthma) by administering to a mammal in need thereof a therapeutically effective amount inhibitor. The administration to a septic patient may be either continuous or intermittent.
The decision to begin the therapy for sepsis will be based upon the appearance of the clinical manifestations of sepsis or laboratory tests which show initiation of the sepsis cascade (inclusive of renal complications or coagulation abnormalities or multiple organ failure). Typical clinical manifestations are fever, chills, tachycardia, tachypnea, altered mental state, hypothermia, hyperthermia, accelerated or repressed breathing or heart rates, increased or decreased white blood cell count, and hypotension. These and other symptoms are well known in the art as set out in standard references such as, Harrison""s Principles of Internal Medicine (ISBN 0-07-032370-4) 1994, pages 511-515.
The decision to determine the length of therapy may be supported by standard clinical laboratory results from commercially available assays or instrumentation supporting the eradication of the symptoms defining sepsis. The method of the invention may be practiced by continuously or intermittently administering a therapeutically effective dose of the inhibitor. The administration can be conducted for up to a total of about 60 days with a preferred course of therapy lasting for up to 10 days.
The decision to end therapy by the method of the invention may be supported by standard clinical laboratory results from commercially available assays or instrumentation or the disappearance of clinical symptoms characteristic of sepsis. The therapy may be restarted upon the return of sepsis. Pediatric forms of sepsis are also successfully treated by the methods, compounds, and formulations of this invention.
When the compound of the present invention is a crystallized, it may show various crystal forms and crystal habits.